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Abstract

Drosophila Elav is the founding member of the conserved family of Hu RNA binding proteins (RBPs), which collectively play critical and diverse roles in post-transcriptional regulation. In particular, Elav has for >20 years served as the canonical neuronal marker, owing to the availability of specific monoclonal antibodies. Surprisingly, although Elav has a well-characterized neural cis-regulatory module, we find endogenous Elav is also ubiquitously transcribed and post-transcriptionally repressed in non-neural settings. In particular, mutant clones of multiple miRNA pathway components derepress ubiquitous Elav protein. Our re-annotation of the elav transcription unit shows that not only does it generate extended 3' UTR isoforms, its universal 3' UTR isoform is much longer than previously believed. This longer common 3' UTR region includes multiple conserved, high-affinity sites for the miR-279/996 family. Notably, out of several miRNA mutants tested, we find that endogenous Elav and a transgenic elav 3' UTR sensor are derepressed in mutant clones of mir-279/996. We also observe cross-repression of Elav by another RBP derepressed in non-neural miRNA pathway clones, namely Mei-P26. Finally, we demonstrate that ubiquitous Elav has regulatory capacity, since derepressed Elav can stabilize an Elav-responsive sensor. It is critical to restrict Elav outside of the nervous system as misexpression of Elav in non-neural territories has profoundly adverse consequences. Altogether, we define unexpected post-transcriptional mechanisms that direct appropriate cell-type specific expression of a conserved neural RBP.

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